Principal Investigator/Program Director (Last, first, middle): Moll, Ute, M Title: the Role of p63 and p73 in Cancer PI: Ute M. Moll, M.D. Abstract p53 controls a powerful stress response and is a quintessential tumor suppressor. The discovery of p63 and p73, two p53 family members, provoked much speculation about their individual and collective functions. However, while a strong consensus exists that both genes play a major role in cancer, current data is conflicting whether their nature is tumor suppressive, oncogenic or in some context both. Although their function in development was immediately apparent from gene ablation studies, delineating their exact role in cancer remains elusive due to a lack of clear genetic data in humans and mice. Due to a second internal promoter and alternative splicing, p63 and p73 are complex bipolar genes giving rise to multiple isoforms that can simplistically be viewed as [unreadable]Two Opposing-Genes-in-One[unreadable]. Moreover, in sharp contrast to the ubiquitous mutational alteration of p53, p63 and p73 are characterized by a virtual absence of inactivating mutations, and instead exhibit aberrant expression of specific isoforms in tumors. This grant aims at elucidating the in vivo role of both genes in specific oncogenic contexts and is based on two premises. First, normal tissues exhibit a striking specificity for tissue types and isoforms in their p63 and p73 expression, an important fact that up to now received little attention, yet likely holds the